Individual differences in alcohol-induced aggression. A nonhuman-primate model.

Some people are more likely than others to become aggressive after consuming alcohol. Researchers studying alcohol use and aggression hope to identify individual differences in behavior and biochemistry that exist among subjects who become aggressive following alcohol consumption. Research with nonhuman primates has shown that individual differences in brain chemistry predict impulsivity, aggression, and alcohol-induced aggression. These differences appear to be associated with early rearing experiences and remain stable throughout the individual's life.


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esearch has demonstrated a con sistent relationship between alco hol use and violent behavior.Both perpetrators and victims of violent crimes are likely to have consumed alco hol prior to certain aggressive acts, such as rape, assault, domestic violence, and murder (Collins and Messerschmidt 1993;Arseneault et al. 2000;Cunradi et al. 1999;Scott et al. 1999).For example, in one study of domestic violence, prior alcohol consumption was likely in cases of phys ical violence but not in cases of verbal aggression, and prior alcohol consump tion by both partners was more likely in episodes of severe violence (Leonard and Quigley 1999).Moreover, high alcohol consumption by couples was predictive of future acts of violence by the male partner (Quigley and Leonard 2000).
Although not all alcoholics are violent, alcoholics are more likely than nonalco holics to have a history of violent behavior (Swanson 1993), and alcohol abuse is a major risk factor in spousal violence and homicide (Soyka 1999).
There appears to be a growing consen sus that alcohol consumption is related to violent behavior and aggression.In an extensive review of violence-related injuries, Cherpitel (1997) reported that compared with other injured emergency room patients admitted at the same time, people with violence-related injuries entering an emergency room were more likely to have a positive blood alcohol concentration (BAC), to report drinking prior to the injury, and to report more frequent heavy drinking and alcoholrelated problems.In addition, recent comprehensive meta-analyses analyzing a high number of studies from differ ent laboratories have concluded that alcohol increases aggression under certain conditions (Bushman 1997;Ito et al. 1996), especially in certain individuals (Zhang et al. 1997).
This article examines the differences in brain chemistry among individuals that influence whether alcohol increases aggression.A nonhuman-primate model is described that has been developed specifically to study these differences and the influence of environment and J. DEE HIGLEY, PH.D., is a research psychologist at the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.

Individual Differences in Alcohol's Effect on Aggression
Although it is widely believed that aggression and alcohol use are strongly related, most people who consume alcohol do so without acting aggressively.Predicting which individuals are likely to exhibit aggression following alcohol con sumption is an important and intriguing research problem.Perhaps the lack of focus on the individual is one of the rea sons why demonstrating a direct causal relationship between alcohol consump tion and aggression has, at times, yielded mixed results (see reviews in Brain 1986; Lipsey et al. 1997).Some researchers have suggested that demonstrating a clear rela tionship between alcohol intake and aggression is difficult, because alcohol consumption increases aggressiveness in some individuals, but decreases it in others (Dougherty et al. 1996;Lipsey et al. 1997;van Erp and Miczek 1997;Winslow et al. 1988;Winslow and Miczek 1985;Zhang et al. 1997).Such mixed findings may be related to researchers' lack of focus on differences among individuals.For example, research indicates a stronger relationship between alcohol consump tion and aggression in subjects with certain traits, including antisocial per sonality (Moeller et al. 1998), alcohol dependency (Arseneault et al. 2000), impaired cognitive functions (Welte and Wieczorek 1998), previous aggressive episodes (Leonard and Quigley 1999), and low levels of the brain chemical serotonin in the central nervous system (CNS) (Dougherty et al. 1999;Hoaken and Pihl 2000;Pihl et al. 1995;Virk kunen et al. 1995).

Animal Models and Individual Differences
Studying alcohol-induced aggression in humans has several limitations (see sidebar).One solution to these problems has been to use animal models.Studies with animal models have helped delin eate how alcohol affects aggression and the mechanisms that induce these changes.For example, using a rodent model, Miczek and colleagues (1993) showed that alcohol's effect on aggression is dose-dependent, increasing aggres sion at low dosages, but decreasing it at higher dosages.This study showed that these effects are not universal, but that wide differences exist between individ uals in the effects of alcohol on aggres sion.The authors found that the same dose of alcohol increased aggression in some subjects, decreased aggression in other subjects, and had no effect on some other subjects.Alcohol's effect on aggres sion was found to be a stable, traitlike response (i.e., the effect was consistent for a given individual, like gregarious ness is a personality trait that is stable between situations and across time).Whether this difference is present in higher animals, such as primates, is the focus of this article.

A Nonhuman-Primate Model
Our laboratory has recently used a nonhuman-primate model to investigate individual differences in the effects of alcohol on aggression.Because nonhuman primates are genetically our closest relatives, findings from these animals are more likely to have relevance to the human condition than findings from other animals.We chose rhesus macaques for our studies because of their close genetic similarity to humans and because they Studies investigating the effects of alcohol on aggression in humans have typically used an experimental approach in which a person consumes alcohol and is then provoked or asked to compete with another person.Aggression is measured when the person is given an opportunity to shock or verbally threaten a competitor.Under such conditions, many studies have found that aggression is more likely to occur after alcohol consump tion (e.g., see Taylor 1993).These studies have outlined a number of possible reasons why alcohol con sumption increases the probability of aggression, and a few studies have focused on individual differences and the variables that induce some people to become aggressive (Gustafson 1991a(Gustafson , 1991b)).
Predicting which individuals will become violent after consuming alcohol in real-world settings remains elusive, however.This may be attrib utable partly to the tenuous relationship between alcohol-induced aggression in the laboratory and real-world alcohol-induced violence.In addition, researchers ethically cannot induce true violence in the labo ratory.Such research in humans also poses problems, because difficulties arise in measuring underlying etiolog ical mechanisms, such as variations in the activity of key chemicals in the brain and inherent biochemical differences that exist among people.

Difficulties in Studying Alcohol-Induced Aggression in Humans
have the most well-characterized CNS of the nonhuman primates.As a conse quence of their genetic similarity to humans, rhesus macaques also display similar neurodevelopment and func tional neuroanatomy and have many neurobiological features that are similar, if not identical, to human neurobiology (Azmitia and Gannon 1986;Berger et al. 1991;Uylings and van Eden 1990).
Rhesus macaques have a similar CNS to humans and, perhaps as a result of this sophisticated CNS, have developed a complex social system.Like that of humans, this social system is based on specific rules for relationships and social behaviors.Moreover, rhesus macaques develop long-lasting social bonds that may endure their life span.For individ uals to live in such societies, they must learn to control their impulses-that is, display proper social behavior at appro priate times, in applicable settings, and modify their behavior depending on the situation and partner with whom they are interacting.
In modeling psychopathology, nonhuman primates offer numerous advan tages.Their rearing histories can be controlled systematically and manipu lated in a manner not possible in humans, thus allowing researchers to test hypothe ses concerning the role of early experi ences.Experimental procedures that are not practical in humans are possible in nonhuman primates.For example, researchers often assess the activity of brain chemicals (i.e., neurotransmitters) by taking samples of the fluid that bathes the brain and spinal cord (i.e., cere brospinal fluid [CSF]).Repeated CSF samples can be readily obtained in a highly controlled fashion to assess sub jects longitudinally.An added advan tage of using nonhuman primates, such as rhesus macaques, is that the developmental process is compressed; they mature four to five times more rapidly than do humans.Thus, developmental outcomes can be studied prospectively in a fraction of the time it takes to com plete a comparable human prospective developmental study.Nonhuman primates are ideal for studying many aspects of human alcohol psychopathology.Never theless, some features of human alcoholrelated psychopathology exist that non-human primates do not model as well as they do some other features.For example, measuring the role of alcohol expectancies on aggression in the nonverbal primate would be difficult.

Serotonin and Impulsivity, Drinking, and Violence
Some clues are emerging that may help identify individuals prone to violence when drinking alcohol and reveal the underlying mechanisms involved in this relationship.Not all alcoholics are aggres sive.Cloninger (1987,1988) has proposed that two subtypes of alcoholism exist, type I and type II.Type I alco holics are believed to consume alcohol primarily to reduce anxiety, whereas alcohol use for type II alcoholics appears to be part of an overall behavior pattern of impulsive, antisocial behavior.Type II alcoholism is, therefore, characterized by impaired impulse control, antisocial traits, difficulties in social relationships, and physically aggressive behaviors (Cloninger 1986(Cloninger , 1987(Cloninger , 1988)).Indeed, Bergman and Brismar (1994) concluded that type II alcoholism is determined by a genetic predisposition to both alcoholism and violence.
Research also indicates that alcoholics who have reduced levels of serotonin in the brain are prone to violent behavior (Virkkunen et al. 1995(Virkkunen et al. , 1994b)), which may be a product of impaired impulse control.Scott and colleagues (1999), for example, found that perpetrators and victims of assault are more likely to score high in impulsivity and that alco hol further heightens the likelihood of violence among such people.Type II alcoholics, sons of alcoholic fathers (Giancola et al. 1993;Limson et al. 1991;Schulsinger et al. 1986;Sher et al. 1991) and, in some studies, daughters of alcoholic fathers (Sher et al. 1991) have scored high on measures of impul sivity and aggression (Tomori 1994).In a series of studies, Virkkunen and col leagues (1995, 1994a, 1994b) found that alcoholic men were particularly prone to violence if they had low con centrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA).After reviewing such findings, Linnoila and colleagues (1994) concluded that excessive alcohol intake and violence in type II alcoholics may both originate from dysfunctional impulse control, which in turn results from impaired serotonin functioning.

A Nonhuman-Primate Model for Type II Alcoholism
Nonhuman primates provide a poten tially relevant animal model to test the assumptions of Cloninger's model, which postulates that high levels of vio lent behavior in alcoholics are associated with impaired serotonin functioning.Like humans, each individual monkey exhibits quantifiable personality traits, and like humans, appropriate early rearing patterns are crucial for norma tive development.When an alcohol solution is palatable, most nonhuman primates, like humans, will freely con sume alcohol.Most subjects consume alcohol at modest levels, but about 20 percent of the subjects will consume alcohol at high levels that produce both visible signs of intoxication and blood alcohol levels above 0.10 percent.During the past decade, we have investigated individual differences in alcohol con sumption in nonhuman primates by studying CNS and temperamental influences on excessive alcohol consump tion.In this effort, we have focused on the relationships between neurophysi ology, impulsivity, aggression, and alco hol consumption.
Research findings suggest that low CSF 5-HIAA concentrations are not correlated with high rates of overall levels of aggression, but only are correlated with high levels of spontaneous, impul sive aggression, which tends to escalate to physically damaging conflicts (Higley et al. 1996c).This association indicates that the high rates of violent aggression shown by these monkeys probably result from impaired impulse control.Furthermore, escalated aggression in subjects with low CSF 5-HIAA concentrations is strongly correlated with measures of impulsivity (Higley et al. 1996b).In addition, alcohol consumption is bingelike and excessive in subjects with low CSF 5-HIAA concentrations (Higley et al. 1996e).
Research using nonhuman primates has been particularly useful, because it has delineated possible underlying mech anisms that produce impaired serotonin functioning.Long-term studies of nonhuman primates in which researchers have repeatedly sampled CSF from the same subjects have shown that individual differences in CSF 5-HIAA concentra tions remain stable over time (Higley et al. 1992b(Higley et al. , 1993;;Kraemer et al. 1989).Furthermore, even under conditions when the settings and situations change, individual differences remain stable.For example, when CSF 5-HIAA is sampled while the subjects live alone in single cages, and then again after they are placed into new social groups, indi vidual differences in CSF 5-HIAA concentrations are positively correlated (Higley et al. 1996a).Furthermore, when 14 CSF samples were obtained over a 1-year period from the same adult female subjects, individual differ ences in the 5-HIAA levels remained consistent over the time period (i.e., the levels had high interindividual sta bility) (Higley et al. 1996a).
This consistent high level of interindi vidual stability is not limited to the laboratory setting, where environmental changes are closely controlled and expe riences are relatively homogeneous.In their natural environment, adolescent male macaques migrate from their birth groups to join new social groups (Higley et al. 1994).This is a period of high social stress, because the young males must form new relationships and face social challenges in which trauma and premature mortality are relatively frequent (Higley et al. 1994).Despite these rather dramatic environmental changes, interindividual differences in CSF 5-HIAA concentrations during the year preceding migration to a new social group are positively correlated with interindividual differences in CSF 5-HIAA concentrations following migration.Such interindividual differ ences also appear to stabilize beginning early in life.CSF 5-HIAA concentra tions were stable when samples were taken from monkeys 14, 30, 60, 90, 120, and 150 days after birth (Shannon et al. 1995).These early differences remain stable, with mean concentrations of CSF 5-HIAA taken in late infancy (i.e., at age 6 months) predicting concentra tions 1 year later in middle childhood (Higley et al. 1992b) and into adulthood (Higley et al. 1996d.Such findings suggest that as a poten tial risk factor, low CSF 5-HIAA con centrations are present early in life and endure over time and across situations.

Influence of the Early Environment on CNS Development
The relationships between serotonin and behavior problems may begin early in life.In one study, pubertal children of alcoholics who exhibited low con centrations of serotonin in their blood received high ratings for behavioral disin hibition and aggression (Twitchell et al. 1998(Twitchell et al. , 2000)).Similarly, children with high ratings on measures of aggression and social deviancy and low ratings on competent social behaviors displayed rel atively low CSF 5-HIAA concentrations (Kruesi et al. 1990).Early events may adversely affect the serotonin systems.
Animal studies have shown that appropriate environmental input dur ing developmental periods is essential for the normal development of the CNS (Black et al. 1989;Greenough 1987).Primate societies are explicitly structured to assure that infants receive such input.When the primate order diverged into Old and New World species, New World species evolved a new system of parental care not typically seen in Old World species.Among most Old World monkey societies, newborns initially develop their social skills within the protective and watchful tutelage of their biological mothers.Mothers are especially important social agents through which infant and juvenile monkeys develop the capacity to properly inhibit and express emotions, including aggres sion (Bernstein and Ehardt 1986;Harlow 1969;Harlow and Harlow 1965;Higley andSuomi 1986, 1989).
In research settings, instances in which peers are the primary teachers of young monkeys (peer-only rearing) have been widely used to study development in monkeys.The subjects are removed from their mothers at birth and reared without adults but with constant access to other age-matched infants.Peer-only reared monkeys exhibit many deficits in impulse control.For example, as ado lescents, when alcohol is freely available, they are prone to excessive alcohol con sumption (Higley et al. 1991a), and during competitive interactions, minor episodes of aggression are more likely to escalate to severe aggression (Higley et al. 1994).
Interaction between young monkeys and adults not only affects the acquisi tion and development of behavior, but also plays a crucial role in the organiza tion and proper development of the CNS.For example, a number of studies using nonhuman primates have shown that early experiences affect serotonin functioning during infancy and child-hood (Higley et al. 1992b(Higley et al. , 1993, 1996e;, 1996e;Kraemer et al. 1989).These studies have shown that adult influence, particularly maternal input, is critical to the develop ment of the CNS serotonin system.In the absence of adult influence, the devel opment of serotonin functioning is impaired.When CSF 5-HIAA was obtained from peer-only reared and mother-reared monkeys 14, 30, 60, 90, 120, and 150 days after birth, parentally neglected, peer-reared subjects exhibited lower CSF 5-HIAA concentrations than did mother-reared subjects (Shannon et al. 1995).One study with a limited sam ple size suggested that the effect of early rearing experiences on CSF 5-HIAA may disappear by adolescence (Higley et al. 1991b).However, in a study in which peer-only reared and mother-reared sub jects were studied from infancy into adulthood, the peer-only reared subjects exhibited lower CSF 5-HIAA concen trations than did the mother-reared sub jects in both infancy and adulthood (Higley et al. 1996e).
Although conclusions may be somewhat preliminary, recent studies indicate that early adverse experiences may affect human as well as nonhuman-primate CNS serotonin functioning.Boys reared in adverse environments, such as with parents who are absent or who show harsh parenting practices, show lower levels of a molecule that binds with serotonin and mediates its activity (i.e., a serotonic receptor) compared with boys reared in better family settings (Pine et al. 1996).In a recent study of adults who had grown up in and were currently living in poverty, researchers used a serotonin-acting drug to stimulate the release of the hormone prolactin and found that these adults released less prolactin than did people reared in better environments (Matthews et al. 2000).Therefore, some evidence indicates that as with nonhuman pri mates, being brought up in a less favorable environment may adversely affect CNS serotonin functioning in humans.

Alcohol and Aggression in Nonhuman Primates
Some studies of nonhuman primates have shown that alcohol increases the probability of aggression in some indi viduals (Winslow and Miczek 1988).Evidence shows that alcohol is more likely to increase aggression in subjects with impaired CNS serotonin function ing.For example, we found that CSF 5-HIAA concentrations were negatively correlated with high ratings for lifetime aggressiveness (Doudet et al. 1995)that is, animals with low CSF 5-HIAA concentrations were more likely to act aggressively throughout life.Moreover, whereas nonhuman primates with low CSF 5-HIAA concentrations are typi cally more likely than others to consume alcohol in excess and exhibit severe aggres sion, the administration of sertraline, a compound that interferes with sero tonin's activity (i.e., a serotonin reuptake inhibitor), reverses these aberrant behav iors by reducing both alcohol consump tion and aggression (Higley et al. 1998).Similarly, administration of the sero tonin precursor tryptophan blocks selfaggression in primates prone to selfabuse (Weld et al. 1999).
Nevertheless, although low CSF 5-HIAA concentrations are correlated with both excessive alcohol consumption and impulsive, violent behavior (e.g., see Higley et al. 1996cHigley et al. , 1996d, 1996e;, 1996e;Mehlman et al. 1994), no long-term studies have been conducted on the relationships between serotonin, a life history of violent behavior, and alcoholinduced aggression.Based on the above studies, we posited that low CSF 5-HIAA concentrations would corre late with high lifetime rates of violent behavior and that a lifetime pattern of violent behavior prior to alcohol exposure would predict aggressive behavior under the influence of alcohol.Such a finding would indicate that individuals who act aggressively under the influence of alcohol have a life-long pattern of aggression, and that in these individu als, alcohol probably increases the like lihood of acting aggressively.
To test this theory, monkeys were given alcohol intravenously to produce modest levels of intoxication (i.e., a blood alcohol concentration of about 0.25 percent).Then each animal was placed into a separate room, and researchers scored each monkey's inci dents of aggressive behavior toward a provoker.To obtain these scores, an investigator entered the room, stood in the opposite corner from the monkey, maintained eye contact, and directed an open-mouth threat face at the mon key every 30 seconds for 5 minutes, a procedure shown to elicit mild aggres sion from macaques (Kalin and Shelton 1989).To test the relationship between lifetime rates of aggression and aggres sion during intoxication, two researchers who had extensive experience observing rhesus monkey behavior independently rated the animals for aggressiveness using the monkeys' medical treatment records.These ratings were based on the frequency of removal from the home cage for perpetrating violent behavior or receiving veterinary care for aggres sion and the frequency and severity of wounds resulting from aggressive encounters.
Animals rated as having a greater lifetime history of severe physical aggression were more likely than others to exhibit higher rates of aggression while intoxicated.Day-to-day homecage competitive aggression-which is used to defend status, tends to be controlled and restrained, and generally does not result in injury-was not cor related with aggression during intoxica tion.A life history of severe traumatic, but not restrained, competitive aggres sion was also predictive of aggression when the animals were intoxicated.Studies investigating humans also show that alcohol is most likely to increase aggression in people already disposed to violent behavior (Zhang et al. 1997).
Both animal and human studies show that rates of aggression during intoxication are stable within individu als (Miczek et al. 1992;Zhang et al. 1997).Similarly, Jaffe and colleagues (1988) found that men who exhibit aggressive behavior when intoxicated are more likely to have had high levels of aggression as children.Our findings suggest that high rates of aggression during intoxication are an extension of a life-long pattern of impulsive, violent aggression, rather than a special form of aggression.This finding is similar to what has been found among men and nonhuman primates with low CSF 5-HIAA concentrations.These studies show that impulsive, severe aggression, but not controlled or competitive aggres sion, is correlated with diminished sero tonin functioning (Coccaro 1989;Higley et al. 1996b;Linnoila et al. 1983).It is noteworthy that in a study of men selected at random from the general population, reducing circulating levels of the serotonin precursor tryptophan augmented rates of alcohol-induced aggression, particularly under condi tions of provocation (Pihl et al. 1995).

Conclusions and Future Directions
As in humans, primates with low CNS serotonergic activity exhibit behaviors indicative of impaired impulse control and unrestrained aggression.The stud ies reviewed here suggest that impaired serotonin functioning may increase the risk for aggression following alcohol consumption.Possibly, a common neu robiological mechanism, such as low sero tonin production and turnover, underlies both excessive alcohol consumption and impulsive aggressive behavior.The reviewed studies also show that interindi vidual differences in the CNS serotonin turnover rate exhibit traitlike qualities and are stable across time and settings, with day-to-day individual differences in CSF 5-HIAA concentrations, for example, showing positive correlations.Such find ings suggest that to the extent that type II psychopathology is mediated by an impaired CNS serotonin system, subjects with low CSF 5-HIAA concentrations may have a long-term risk for type II psy chopathology and alcohol-mediated vio lence that can be detected early in life.Maternal and paternal genetic influences play major roles in producing low CNS serotonin functioning beginning early in life.These genetic influences on serotonin functioning are exacerbated by early rear ing experiences, particularly parental deprivation, thus affecting the risk for type II alcohol psychopathology.
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